Stereoselective synthesis of metyrosine

ABSTRACT

Provided herein are compositions including diastereomers in substantially diastereomerically pure form and enantiomers in substantially enantiomerically pure form, and processes for preparing them and converting them to metyrosine.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application claims priority from U.S. Provisional Application61/256,926, filed Oct. 30, 2009, incorporated herein by reference in itsentirety.

FIELD

The present technology relates to compositions and processes useful forthe stereoselective synthesis of metyrosine and relates generally to thefield of organic chemistry.

BACKGROUND

Metyrosine, which has the structure of Formula:

is useful in reducing elevated levels of catecholamines associated withpheochromocytoma, and preventing hypertension. Metyrosine, as shown, isa chiral compound. The synthesis of metyrosine in pure or substantiallypure enantiomeric form requires a process that involves usingsubstantially diastereomerically and/or enantiomerically pureintermediates. The Applicant has discovered, surprisingly, certaincompounds that are substantially diastereomerically or enantiomericallypure and processes to prepare them, and which compounds may be convertedto metyrosine.

SUMMARY

Compositions are provided that include diastereomers in substantiallydiastereomerically pure form and enantiomers in substantiallyenantiomerically pure form. Processes are provided for preparing thediastereomers and enantiomers. Processes for converting thediastereomers and enantiomers to metyrosine are also provided.

In one aspect, a process is provided for the synthesis of a compound ofFormula II:

including contacting in a solution a compound of Formula I:

wherein R¹ includes C₁-C₄ alkyl with a compound of Formula

or an acid addition salt thereof, in the presence of cyanide (CN⁻), toprovide a product including the compound of Formula II or an acidaddition salt thereof in at least about 55% diastereomeric purity. Insome embodiments, R¹ is methyl. In some embodiments, the process alsoincludes contacting the product including at least about 55%diastereomeric purity of the compound of Formula II or an acid additionsalt thereof with a hydrolyzing agent selected from an acid, a base, ahydroperoxide, or an enzyme to provide a compound of Formula III:

or an acid addition salt thereof in about 100% diastereomeric purity.

In some embodiments, the product precipitates from solution.

In some embodiments, the hydrolyzing agent includes a Brønsted acid.

In some embodiments, the process also includes hydrogenolyzing thecompound of Formula III or an acid addition salt thereof to provide acompound of Formula V:

or an acid addition salt thereof.

In another aspect, a process is provided for the purification of acompound of Formula IV-A:

including re-crystallizing a mixture of diastereomers of Formula IV:

or acid addition salts thereof wherein R¹ includes C₁-C₄ alkyl toprovide the compound of Formula IV-A in at least about 70%diastereomeric purity. In some embodiments, the re-crystallizing isperformed using a solvent system including isobutyl alcohol. In someembodiments, R¹ is methyl.

In some embodiments, the process also includes hydrogenolyzing thecompound of Formula IV-A or an acid addition salt thereof to provide acompound of Formula V:

or an acid addition salt thereof In some embodiments, the compound ofFormula V or an acid addition salt thereof is at least about 80%enantiomeric purity after isolation.

In some embodiments, the process also includes contacting the compoundof Formula V or an acid addition salt thereof with an acid to provide acompound of Formula

or an acid addition salt thereof.

In another aspect, a process is provided for the synthesis of a compoundof Formula VIII:

including contacting a compound of Formula VI:

wherein R² includes substituted or unsubstituted aryl and each R³includes independently C₁-C₃ alkyl with O-allyl-N-benzylcinchonidiniumbromide, a metal hydroxide, or a metal carbonate, and a compound ofFormula VII:

wherein Z¹ includes a leaving group and R¹ includes C₁-C₄ alkyl toprovide a compound of Formula VIII in at least about 60% enantiomericpurity. In some embodiments, the compound provided is of Formula:

In some embodiments, the compound of Formula VII is4-methoxybenzyliodide, 4-methoxybenzylbromide, or4-methoxybenzylchloride.

In some embodiments, the process also includes contacting the compoundof Formula VIII with a hydrolyzing agent to provide a compound ofFormula IX:

or an acid addition salt thereof. In some embodiments, the hydrolyzingagent includes a Brønsted acid.

In some embodiments, the process also includes contacting the compoundof Formula IX or an acid addition salt thereof with an acid to providethe compound of Formula

or a salt thereof In some embodiments, the acid includes a Lewis acid.

In another aspect, an isolated stereoisomer of Formula X is provided:

or an acid addition salt thereof; wherein: R¹ includes C₁-C₄ alkyl; R⁴includes —CN or —CONH₂,R⁵ is hydrogen or

and R⁶ is Me or —CONH₂ provided however that if R⁶ is Me then R⁴ is—CONH₂, and wherein the stereoisomer of Formula X is at least about 70%diastereomerically pure after isolation, provided however that if R⁵ isH, then the stereoisomer of Formula X is at least about 50%enantiomerically pure after isolation.

In some embodiments, the compound of Formula X is a compound of FormulaX-A or X-B or an acid addition salt of either of the following:

which is at least about 80% diastereomerically pure. In someembodiments, R¹ is methyl.

In some embodiments, the compound of Formula X is a compound of FormulaV or an acid addition salt thereof:

which is at least about 80% enantiomerically pure. In some embodiments,R¹ is methyl.

In another aspect, an isolated enantiomer of Formula XI is provided:

or an acid addition salt thereof; wherein: R₁ includes C₁-C₄ alkyl; R₂includes unsubstituted or substituted aryl; each R³ independentlyincludes C₁-C₃ alkyl; and R⁷ includes —NH₂ or

and wherein the enantiomer of Formula XI is at least about 60%enantiomerically pure after isolation.

In another aspect, an isolated enantiomer of Formula XI-A is provided:

or an acid addition salt thereof.

In some embodiments, the isolated enantiomer Formula XI-B is provided:

or an acid addition salt thereof wherein R⁸ is halogen.

DETAILED DESCRIPTION Definitions

The following definitions are provided to assist the reader. Unlessotherwise defined, all terms of art, notations, and other scientific ormedical terms or terminology used herein are intended to have themeanings commonly understood by those of skill in the chemical arts. Insome cases, terms with commonly understood meanings are defined hereinfor clarity and/or for ready reference, and the inclusion of suchdefinitions herein should not be construed as representing a substantialdifference over the definition of the term as generally understood inthe art.

“Acid” refers to a Brønsted acid or a Lewis acid.

“Alkyl” refers to a straight or branched chain alkyl group. “C₁-C₄alkyl” refers to a substituted or unsubstituted straight or branchedchain alkyl groups having 1-4 carbon atoms. C₁-C₄ alkyl groups include,for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, andtert-butyl.

“Aryl” refers to a cyclic moiety that includes one or more monocyclic orfused ring aromatic systems. Such moieties include any moiety that hasone or more monocyclic or bicyclic fused ring aromatic systems,including but not limited to phenyl and naphthyl.

“Brønsted Acid” refers to a compound that can donate a proton (H+).Examples of Brønsted acids include, without limitation, hydrochloricacid, hydrobromic acid, sulfuric acid, and various sulfonic acids.

“(C_(m)-C_(n))”, “C_(m)-C_(n)”, or “C_(m-n)” refer to the number ofcarbon atoms in a certain group before which one of these symbols areplaced. For example, C₁-C₃ alkyl refers to an alkyl group containingfrom 1 to 3 carbon atoms.

“Halogen” or halo” refers to, by themselves or as part of anothersubstituent, unless otherwise stated, a fluorine, chlorine, bromine, oriodine atom.

“Hydrogenolyzing” refers to cleaving a heteroatom-benzylic orsubstituted benzylic (substituted on the phenyl and/or the methylenegroups) bond by adding hydrogen and producing a heteroatom-H (such as anO—H, N—H, or S—H) moiety. Hydrogenolysis is a way to deprotect aprotected amino, hydroxyl, carboxyl, or mercapto functionality. Variousmethods of hydrogenolyzing a nitrogen-benzylic or nitrogen-substitutedbenzylic moiety, are known to one of skill in the art and reported, forexample, and without limitation, in Wuts et al., Greene's ProtectiveGroups in Organic Synthesis, 4th Edition, 2006.

“Leaving group” refers to an atom or a group that can be replaced by anucleophile. Examples of leaving groups include, but are not limited to,halide and sulfonate.

“Lewis acid” refers to a compound that can accept a lone electron pair.Examples of Lewis acids include, without limitation, B(R^(y))₃ whereineach R^(y) independently is halogen, alkyl, alkoxy, or aryl.

“Substituted” refers to a group as defined herein in which one or morebonds to a hydrogen are replaced by a bond to non-hydrogen“substituents” such as, but not limited to, acetyl, carboxylic acid orcarboxylate ester, halogen atom, trifluoromethyl, methoxy, and —NH₂ andits mono and dialkylated derivatives. Aryl groups may also besubstituted with alkyl or substituted alkyl groups.

“Sulfonate” refers to a group of Formula —OSO₂R^(x) wherein R^(x) isalkyl, trifluoromethyl, or substituted or unsubstituted aryl.

In one aspect, isolated stereoisomers of Formula X are provided:

or a salt thereof; where R¹ is C₁-C₄ alkyl; R⁴ is —CN or —CONH₂; R⁵ ishydrogen or

and R⁶ is Me or —CONH₂, provided that when R⁶ is Me R⁴ is —CONH₂, andwhere the isolated stereoisomer of Formula X is greater than 50%diastereomerically pure; and further provided that where R⁵ is H theisolated stereoisomer of Formula X is greater than 50% enantiomericallypure. In one embodiment, R¹ is Me.

In one embodiment, the isolated stereoisomer is a compound representedFormula X-D:

where R¹, R⁴, and R⁶ are as defined for Formula X, above. In someembodiments, a composition is provided including the isolatedstereoisomer of Formula X-D in at least about 75% diastereomeric purity.In some such embodiments, this includes providing the isolatedstereoisomer of Formula X-D in at least about 80%, at least about 85%,at least about 90%, at least about 98%, or at least about 99%diastereomeric purity. In another embodiment, R⁶ is Me. In anotherembodiment, R⁶ is —CONH₂. In another embodiment, R¹ is Me.

In another embodiment, the isolated diastereomers of Formula X-A and X-Bare provided:

wherein R¹ and R⁴ are defined as in Formula X above, in at least 80%diastereomerically pure form. In another embodiment, R¹ is Me. Inanother embodiment, the isolated diastereomer is X-A and it is at leastabout 75% diastereomerically pure. In some such embodiments, theisolated diastereomer is X-A and it is at least about 80%, at leastabout 85%, at least about 90%, at least about 98%, or at least about 99%diastereomerically pure. In another embodiment, the isolateddiastereomer is X-B and it is at least about 55% diasteromerically pure.In some such embodiments, the isolated diastereomer X-B is at leastabout 60%, at least about 70%, at least about 75%, at least about 80%,at least about 85%, at least about 90%, at least about 98%, or at leastabout 99% diastereomerically pure.

In another embodiment, the isolated diastereomer is of Formula II:

In another embodiment, the isolated diastereomer is of Formula III:

In certain embodiments, R¹ is Me.

As used here, “diastereomerically pure” refers to the mole % of acertain diastereomer in a mixture of such diastereomers. For example,and without limitation, where the compound of Formula X-A is provided inabout 80% diastereomerically pure form, it may also include about 20% ofthe diastereomer of Formula X-E:

In this example, the diastereomeric excess (or “de”) of the X-Adiastereomer in the mixture of diastereomers is about (80-20)% or about60%.

Similarly, for example, and without limitation, the compound of FormulaX-B may be provided in about 80% diastereomerically pure form, whichincludes about 20% of the diastereomer having Formula X-F:

Similarly, for example, and without limitation, a compound of FormulaX-D which is about p % diastereomerically pure, includes about (100−p)%of a diastereomer of Formula, X-G:

Therefore, in certain embodiments, compositions are provided containingin greater than about 50% diastereomeric purity, the (S,S) diastereomersof Formula X-A:

Also, in certain embodiments, compositions arc provided containing ingreater than about 50% diastereomeric purity, the (S,R) diastereomers ofFormula X-B:

In a certain embodiment, R⁴ is —CONH₂. In certain other embodiments, R¹is methyl.

In another embodiment, an isolated S-enantiomer of Formula V isprovided:

in at least about 75% to at least about 80% enantiomerically pure form.In another embodiment, the isolated enantiomer of Formula V is providedin at least about 85%, at least about 90%, at least about 98%, or atleast about 99% enantiomerically pure form. In another embodiment, acomposition is provided including at least about 75% of the compound ofFormula V, which is the S-enantiomer. In certain embodiments withinthese embodiments, R¹ is methyl.

As used here, enantiomerically pure refers to the mole % of a certainenantiomer in a mixture of such enantiomers. The rest of the isolatedcomposition may, for example and without limitation, substantially, bethe other enantiomer. For example, and without limitation, thecompositions containing about 80% of the S enantiomer of Formula Vprovided in an embodiment of the present technology, includes, about 20%of the R-enantiomer of Formula V-A:

In this example, the enantiomeric excess (or “ee”) of the V enantiomerin the mixture of enantiomers is about 60%.

In another aspect, an isolated S-enantiomer of Formula XI is provided:

or a salt thereof where R₁ is C₁-C₄ alkyl; R⁷ is —NH₂ or

R₂ is unsubstituted or substituted aryl, and each R³ independently isC₁-C₃ alkyl, and wherein the isolated S-enantiomer of Formula XI isgreater than 60% enantiomerically pure. In another embodiment, theisolated enantiomer is of Formula XI-A:

or a salt thereof. In another embodiment, the isolated enantiomer is ofFormula XI-B:

or a salt thereof wherein R⁸ is halo. In certain embodiments, R¹ is Me.In another embodiment the isolated enantiomers are of Formulas:

or salts thereof.

The various isolated diastereomers, and isolated enantiomers, andcompositions including them, are prepared according to processesprovided in other aspects and embodiments of the present technology, andusing certain processes which are well known to one of skill in the art.For example, and without limitation, see Schemes 1 and 2 below. Thevarious diastereomers and enantiomers may be isolated in a number ofways including, but not limited to, crystallization, chromatographicseparation, precipitation, and combinations thereof, as also describedherein below and/or known to one of skill in the art. The determinationof diastereomeric or enantiomeric purity and the diastereomeric orenantiomeric excess of an isolated composition containing a mixture ofdiastereomers or enantiomers is performed by using a number of methodsincluding, but not limited to, NMR (with or without chiral resolvingagents, as appropriate), chromatography (using chiral columns fordetermining enantiomeric purity), polarimetry, and circular dichroism.

An acid salt of the starting material of each step may also be used forcertain of the transformations shown in Scheme 1.

In one aspect, a process is provided for the synthesis of a compound ofFormula II:

including contacting in a solution a compound of Formula I:

wherein R¹ is C₁-C₄ alkyl with (R)-phenylglycinamide or an acid saltthereof, in the presence of cyanide (CN) to provide a precipitate whichincludes the compound of Formula II in at least about 55% diastereomericpurity. (R)-phenylglycinamide is represented as:

In another embodiment, the precipitate includes at least about 60%, atleast about 65%, at least about 70%, at least about 75%, at least about80%, at least about 85%, at least about 90%, at least about 95%, or atleast about 98% of the compound of Formula II. In another embodiment,the precipitate includes the compound of Formula II in at least about60%, at least about 65%, at least about 70%, about 75%, at least about80%, at least at least about 85%, at least about 90%, at least about95%, or at least about 98% diastereomeric purity. Thus, in certainembodiments, processes are provided for the synthesis of a compound ofFormula II in a substantially diastereomerically pure form. In someembodiments, the cyanide source is an alkali metal cyanide such as KCNor NaCN.

In one embodiment, the contacting is performed at about 15° C. to about60° C. In other embodiments, the contacting may also be performed atlower temperatures, wherein, the time period of the contacting may be oflonger duration than those at 15° C. or higher. In another embodiment,the solution is an aqueous solution. In another embodiment, the aqueoussolution further includes a lower alkanol. In another embodiment, thelower alkanol is methanol. In another embodiment, the contacting isperformed for about 5 h to about 20 days, about 10 h to about 10 days,about 20 h to about 5 days, and about 2 days to about 4 days. In oneembodiment, the precipitate is collected by filtration. Volatiles may beremoved from the collected precipitate in vacuo. In one embodiment, R¹is methyl.

In another embodiment, the process may also include contacting theprecipitate including the compound of Formula II or an acid saltthereof, with a hydrolyzing agent to provide an isolated compound ofFormula III:

or an acid salt thereof in substantial diastereomeric purity. In anotherembodiment, the hydrolyzing agent is an acid, a base, a hydroperoxide,or an enzyme. In other embodiments, the hydrolyzing agent may include anoxidizing agent. In one embodiment, the acid is a Brønsted acid. Inanother embodiment, the Brønsted acid is sulfuric acid. In anotherembodiment, the sulfuric acid contains up to 10% weight/weight water. Inanother embodiment, the Brønsted acid is a sulfonic acid, hydrogenhalide, or a carboxylic acid. In another embodiment, the Brønsted acidis CF₃SO₃H, HCl, polyphosphoric acid, or HOAc. In another embodiment,the Lewis acid is Al₂O₃, BF₃, or TiCl₄. In another embodiment, thecontacting is performed at a temperature of about −25° C. to about 5° C.In one embodiment, the contacting is performed in a solution. A varietyof solvent systems may be used for preparing the solution. In oneembodiment, the solvent system includes a chlorinated solvent. Inanother embodiment, the chlorinated solvent is dichloromethane. Othersteps, well known to one of skill in the art, such as neutralization,separation of organic and aqueous phases, and isolation of the product,are also performed as needed during the above preparation, as will beapparent to one of skill in the art upon reading this disclosure in itsentirety. In another embodiment, the compound of Formula III is obtainedin a diastereomeric purity of at least 80%. In another embodiment, thecompound of Formula III is isolated in a composition including at least80% of the compound of Formula III. In another embodiment, R¹ is methyl.

In another embodiment, the process further includes increasing thediastereomeric excess of the compound of Formula III in a diastereomericmixture by crystallization. In one embodiment, diastereomers of Formula

are crystallized to provide the isolated diastereomer of Formula

or acid salts thereof in substantial diastereomeric purity.

In one embodiment, the crystallizing is performed by dissolving thecompound of Formula III in a solvent system including a ketone. In oneembodiment, the ketone is methyl isobutyl ketone. Other solvent systemsmay include an aromatic solvent, a lower alkanol, or an ether. In otherembodiments, the solvent system includes toluene, isopropyl alcohol, orisobutyl alcohol. In another embodiment, the dissolving is performed bydissolving the compound in a refluxing solvent. In another embodiment,the dissolved solution is concentrated before the substantiallydiastereomerically pure compound of Formula III separates as a solidfrom the solution. The process of crystallization may be repeated morethan once, for example and without limitation, up to 10 times to providethe compound of Formula III in high diastereomeric purity (or in highdiastereomeric excess, or de). In another embodiment, R¹ is methyl.

In another aspect, the present technology provides a process for thepurification of a compound of Formula IV-A or an acid salt thereof:

including crystallizing a mixture of diastereomers of Formula IV or acidsalts thereof:

wherein R¹ is C₁-C₄ alkyl to provide the crystallized compound ofFormula IV-A or an acid salt thereof in at least about 70%diastereomeric purity. The diastereomers represented by Formula IV orsalts thereof are essentially diastereomeric compounds of Formula IV-Aand Formula IV-B or salts thereof:

In certain embodiments, the mixture of diastereomers of Formula IVincludes the diastereomer of Formula IV-A in about 50%, about 55%, about60%, about 65%, about 70%, diastereomeric purity. Diastereomericmixtures of Formula IV including the diastereomer of Formula IV-A inmore than 50% diastereomeric purity, may also be purified in accordancewith the processes described herein. In another embodiment, thecrystallizing is performed using a solvent system including isobutylalcohol. In another embodiment, the solvent system includes isopropylalcohol. In another embodiment, the solvent system includes methylisobutyl ketone. In another embodiment, the solvent system includesisopropyl alcohol and methyl isobutyl ketone. In another embodiment, R¹is Me. The process of crystallization may be repeated more than once,for example and without limitation, up to 10 times, to provide thecompound of Formula IV-A in high diastereomeric purity (or in high“de”).

In another embodiment, the present technology provides a processincluding hydrogenolyzing the compound of Formula III and IV-A ofsubstantial diastereomeric purity as provided in various aspects andembodiments of the present technology or acid salts thereof to provide acompound of Formula V:

or an acid salt thereof in substantial enantiomeric purity. In oneembodiment, the hydrogenolyzing is performed using catalytichydrogenation. Catalytic hydrogenation is performed using hydrogen and asuitable Pd catalyst. In another embodiment, the palladium catalyst isPd/C (Pd on charcoal). In one embodiment, the Pd catalyst includeswater. In another embodiment, the hydrogenolyzing is performed bytransfer hydrogenation wherein, during catalytic hydrogenation, acompound other than molecular hydrogen is employed as the source ofhydrogen. In another embodiment, the molecule other than hydrogen thusemployed is formic acid or a formate salt. In another embodiment, thehydrogenolyzing was performed essentially using HCO₂H or NH₄HCO₂ and aPd catalyst. In another embodiment, the Pd catalyst is Pd/C. In anotherembodiment, the process further includes performing the hydrogenolyzingin a solvent system. In another embodiment, the solvent system includesa lower alkanol. In another embodiment, the lower alkanol is EtOH. Othermethods of hydrogenolyzing may be employed in accordance with thevarious process embodiments of the present technology, upon reading thisdisclosure in its entirety. In another embodiment, the compound ofFormula V provided is isolated in at least about 80% enantiomericpurity. In another embodiment, R¹ is methyl.

In another embodiment, a process is provided which includes contactingthe compound of Formula V with an acid to provide metyrosine, which hasa Formula:

or a salt thereof. In another embodiment, the acid is a Lewis acid. Inanother embodiment, the Lewis acid is a trivalent boron based Lewisacid. In another embodiment, the trivalent boron based Lewis acid isBBr₃.

Certain other compounds and processes to make them are schematicallydescribed below.

Thus, in another aspect, the present technology provides a process forthe synthesis of a compound of Formula VIII:

including contacting a compound of Formula VI:

wherein R² is substituted or unsubstituted aryl andeach R³ is independently C₁-C₃ alkylwith O-allyl-N-benzylcinchonidinium bromide, a base including a metalhydroxide or a metal carbonate, and a compound of Formula VII:

wherein Z¹ is a leaving group and R¹ is C₁-C₄ alkyl to provide acompound of Formula VIII isolated in at least 60% enantiomeric purity(enantiomeric excess or ee of 20%).

In one embodiment, the contacting is performed at contactingtemperatures of about 5° C., about 0° C., and about −5° C. In anotherembodiment, after the contacting, the temperature may be raised to atemperature above the contacting temperature. In another embodiment, thecontacting is performed in a solvent system including an aromaticsolvent. In another embodiment, the aromatic solvent is toluene. Inanother embodiment, R¹ is methyl. Other steps, well known to one ofskill in the art, including, but not limited to, neutralization ofreaction mixtures, separation of organic and aqueous phases, andisolation of the product, are also performed as needed as will beapparent to one of skill in the art upon reading this disclosure in itsentirety.

In another embodiment, the compound provided is of Formula XI-B:

or a salt thereof wherein R⁸ is a halogen. In another embodiment, R¹ ismethyl. In another embodiment, the compound provided is of Formula:

In another embodiment, the compound of Formula VII is4-methoxybenzyliodide, 4-methoxybenzylbromide, or4-methoxybenzylchloride.

In another embodiment, the process also includes contacting the compoundof Formula VIII with an acid to provide a compound of Formula IX:

or an acid salt thereof. In one embodiment, the acid contacted is aBrønsted acid. In another embodiment, the Brønsted acid is hydrochloricacid. In another embodiment, R¹ is methyl.

In another embodiment, the process further includes contacting thecompound of Formula VIII with an acid to provide metyrosine or a saltthereof in substantial enantiomeric purity. In another embodiment, theacid is a Brønsted acid. In another embodiment, the Brønsted acid isHBr. In another embodiment, the acid is a Lewis acid. In anotherembodiment, the Lewis acid is BBr₃.

In another embodiment, the process further includes contacting thecompound of Formula IX with an acid to provide the compound of Formula

or a salt thereof in substantial enantiomeric purity. In one embodiment,the acid is a Lewis acid. In another embodiment, the Lewis acid is BBr₃.

In addition to the processes provided as certain aspects and embodimentsof the present technology, steps well known to one of skill in the art,such as, neutralization, separation of organic and aqueous phases, andisolation of the product, may also be performed for preparing thecompounds as described above, and will be apparent to one of skill inthe art upon reading this disclosure in its entirety.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

All publications, patent applications, issued patents, and otherdocuments referred to in this specification are herein incorporated byreference as if each individual publication, patent application, issuedpatent, or other document was specifically and individually indicated tobe incorporated by reference in its entirety. Definitions that arecontained in text incorporated by reference are excluded to the extentthat they contradict definitions in this disclosure.

The present invention, thus generally described, will be understood morereadily by reference to the following examples, which are provided byway of illustration and are not intended to be limiting of the presentinvention.

EXAMPLES

The following abbreviations are used in the examples:

[a] Specific rotation

AUC Area under curve

BINOL 1,2-Bi-2-naphthol

DMSO Dimethyl sulfoxide

dr Diastereomeric ratio

ESI Electrospray ionization

HPLC high performance liquid chromatography

iBu Isobutyl

IPA Isopropyl alcohol

iPr Isopropyl

Me Methyl

MHz Mega hertz

MIK Methyl isobutyl ketone

MS Mass spectrometry

MTBE Methyl tertiary butyl ether

mM Milli molar

mmol Milli mole

NMR Nuclear magnetic resonance

Pd/C Palladium on charcoal

R and/or S Used to denote the stereochemistry of a chiral centeraccording to the Cahn Ingold Prelog priority rules

t_(R) Retention time

Preparation of Metyrosine using (R)-Phenylglycinamide. The generalsynthetic outline is provided by Scheme 3.

Example 1 (R)-Phenylglycinamide.HCl

To a 500 mL flask were charged (R)-phenylglycinamide (20.0 g, 133 mmol,1 eq. Amplachem ref: Aa-33365) and MeOH (160 mL). 4 M HCl/dioxane (50mL, 200 mmol, 1.5 eq.) was then added dropwise resulting in theformation of a white precipitate. The mixture was stirred for 30 min,was filtered and was washed with MeOH (20 mL) and diethyl ether (20 mL).Drying in vacuo provided (R)-phenylglycinamide.HCl (21.9 g, 89%) as awhite solid. ¹H NMR (D₂O, 400 MHz) 4.97 (s, 1H); 7.36-7.41 (m, 5H).

Example 22-[1-(S)-Cyano-2-(4-methoxyphenyl)-1-methylethylamino]-2-(R)-phenylacetamide2

Method A. To a 500 mL flask were charged (R)-phenylglycinamide.HCl (15.0g, 80.6 mmol, 1 eq.), MeOH (104 mL), H₂O (17 mL) andp-methoxyphenylacetone (12.4 mL, 80.6 mmol, 1 eq, Aldrich, ref:19917-6). To this mixture was added a solution of NaCN (3.95 g, 80.6mmol, 1 eq.) in H₂O (10 mL). The resulting solution was stirred for 4days at room temperature while a white precipitate formed. Theprecipitate was filtered and washed with H₂O/MeOH (7:3) to provide2-[1-(S)-cyano-2-(4-methoxyphenyl)-1-methylethylamino]-2-(R)-phenylacetamide2 (11.0 g) as a white solid. The filtrate was stirred for 3 d more atroom temperature and the solid formed was filtered to provide 2 (3.30g). The filtrate was stirred for 1 d more to provide 2 (1.70 g). Thefiltered solids were combined and dried in vacuo to provide 2 (16.0 g,61%, dr 98/2) as a white solid.

Method B. In a sealed tube were charged (R)-phenylglycinamide.HCl (1.2g, 6.45 mmol, 1 eq.), MeOH (4 mL), H₂O (7 mL) and p-methoxyphenylacetone(991 μL, 6.45 mmol, 1 eq.). A solution of NaCN (316 mg, 6.45 mmol, 1eq.) in H₂O (1 mL) was added. The mixture was stirred for 20 hours at40° C. resulting in the formation of a white precipitate. Theprecipitate was filtered, was washed with H₂O/MeOH (7:3 v/v, 2×2 mL) andwas dried in vacuo to provide 2 (1.59 g, 76%, dr 98/2) as a white solid.¹H NMR (CDCl₃, 400 MHz) 1.14 (s, 3H); 2.90 (d, J=13.6 Hz, 1H); 2.99 (d,J=13.6 Hz, 1H); 3.20 (bs, 1H); 3.80 (s, 3H); 4.51 (s, 1H); 5.45 (bs,1H); 5.75 (bs, 1H); 6.90 (d, J=8.6 Hz, 2H); 7.27 (d, J=8.6 Hz, 2H);7.30-7.50 (m, 5H). dr determination: ¹H NMR comparing integration ofpeaks of 2 at 2.90/2.99 (1.98H, formally 2H) with those of itsdiastereoisomer or diastereomer (prepared from racemicphenylglycinamide) at 2.82/2.85 (0.04H, formally 2H). ¹H NMRdiastereoisomer of 2 (CDCl₃, 400 MHz) 1.49 (s, 3H); 2.82 (d, J=13.8 Hz,1H); 2.85 (d, J=13.8 Hz, 1H); 3.78 (s, 3H); 4.52 (s, 1H); 5.55 (bs, 1H);6.60 (bs, 1H); 6.84 (d, J=8.6 Hz, 2H); 7.17 (d, J=8.6 Hz, 2H); 7.30-7.40(m, 5H).

Example 32-[(R)-(Carbamoylphenylmethyl)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide3

To a 500 mL flask were added nitrile 2 (10.0 g, 30.95 mmol) and CH₂Cl₂(130 mL). The solution was cooled to −10° C. and H₂SO₄ (10 mL) was addeddropwise over 15 min. The mixture was stirred for 2 h at 0° C. Ice (200g) was added and the mixture was stirred for 1 h. The mixture wasbasified with 32% aq NH₃ to pH 8-9, EtOAc (400 mL) was added and thephases were separated. The aqueous phase was extracted with EtOAc (2×250mL). The combined organic phases were dried over MgSO₄ and wereconcentrated to provide 3 (11.1 g (9.99 g theoretical, the samplecontains 10% w/w of EtOAc by NMR) 94%, 92.9% chemical purity, 97% de byHPLC/MS) as a white solid. HPLC/MS t_(R)=3.04 min; m/z=342.1 (M+1)

de determination: HPLC/MS comparing integration of peaks at t_(R)=3.04min (98.5 area %) and t_(R)=2.92 min (1.5 area % the otherdiastereoisomer of 3) HPLC/MS diastereoisomer of 3 t_(R)=2.92 min;m/z=342.1 (M+1)

Example 4

Purification of 3 by Crystallization. Amide 3 (8.10 g, 23.7 mmol) andmethyl isobutyl ketone (124 mL) were heated to reflux temperature untilthe solid was dissolved and the solution was cooled to room temperature.The solid formed was filtered, was washed with methyl isobutyl ketone(2×20 mL) and was dried in vacuo to provide 3 (5.45 g, 67%, >99.5%purity by HPLC/MS) as a white solid. ¹H NMR (DMSO, 200 MHz) 1.00 (3H,s); 2.35 (bs, 1H); 2.75 (d, J=13.3 Hz, 1H) 2.85 (d, J=13.3 Hz, 1H); 3.61(s, 3H); 4.17 (s, 1H); 6.60 (d, J=8.4 Hz, 2H); 691 (d, J=8.4 Hz, 2H);6.93 (bs, 1H), 7.01 bs (1H); 7.20-7.50 (m, 6H); 7.6 (bs, 1H). HPLC/MSm/z=342.1 (M+1)

Example 5 2-(S)-Amino-3-(4-methoxyphenyl)-2-methylpropionamide 4

Method A, Hydrogenolysis: Amine 3 (6.00 g, 17.6 mmol, 1 eq) wasdissolved in MeOH (60 mL) and 10% Pd/C (2.15 g, 56% moisture content, 16wt %) was added. The mixture was stirred under H₂ (3 bar) at 50° C. for16 h. The mixture was filtered through Celite, the filter pad was washedwith MeOH (20 mL) and the filtrates were concentrated to provide 5.50 gof a 1:1 mixture of 4 (3.37 g, 91%) and phenylacetamide as a whitesolid.

Method B, Transfer hydrogenolysis: Amine 3 (500 mg, 1.47 mmol, 1 eq) wasdissolved in i-PrOH (5 mL) under Argon. 10% Pd/C (200 mg, 56% moisturecontent, 18 wt %) and ammonium formate (601 mg, 9,56 mmol, 6.5 eq.) wereadded. The mixture was stirred at reflux temperature for 1 h. Themixture was filtered through Celite, the filter pad was washed with EtOH(10 mL) and the filtrates were concentrated to provide 480 mg of a 1:1mixture of desired compound (293 mg, 96%) and phenylacetamide as a whitesolid. ¹H NMR (DMSO, 400 MHz) 1.14 (s, 3H); 2.10 (bs, 2H); 2.50 (d,J=13.1 Hz, 1H); 2.95 (d, J=13.1 Hz, 1H); 3.69 (s, 3H); 6.80 (d, J=8.5Hz, 2H); 6.81 (bs, 1H); 6.90 (bs, 1H); 7.09 (d, J=8.5 Hz, 2H).(Phenylacetamide 3.34 (s, 2H); 7.15-7.28 (m, 6H); 7.42 (bs, 1H).).HPLC/MS 4 t_(R)=1.96 min. MS (ESI (+)) m/z=164.2 (M-CONH₂).(Phenylacetamide t_(R)=1.76 min. MS (ESI (+)) m/z=136.2 (M+1)).

Example 6 Metyrosine 1

To a 100 mL flask with a reflux condenser was charged amide 4 (5.50 g ofa mixture containing 4 (3.37 g, 16.1 mmol) and phenylacetamide (2.13 g))and 48% HBr (30 mL). The solution was heated for 5 h at 120° C. and wascooled to room temperature. H₂O (60 mL) was added and the solution waswashed with EtOAc (3×35 mL). The aqueous phase was concentrated in vacuoto provide a beige paste. The paste was dissolved in H₂O (15 mL) and theresulting mixture was heated to 65° C. Activated carbon (300 mg, TypeNORIT SX) was added and the mixture was stirred for 15 min, was filteredand the filter pad was washed with water (2×4 mL). The combinedfiltrates were heated to 55° C. and the pH was adjusted to 5-6 using 32%aq. NH₃. The mixture was cooled to 0° C., was stirred for 15 min and wasfiltered. The collected solids were washed with cold water (2×5 mL) andwere dried in vacuo to provide (−)-α-methyl-L-tyrosine (or metyrosine) 1(2.65 g, 84%) as a white solid. HPLC (Zorbax C18, NaH₂PO₄ 10 mMpH=3/MeCN (100:0) 10 min, (100:0) to (0:100) 15 min, 0:100 5 min)t_(R)=10.1 min. Chiral HPLC (Nucleosil Chiral-1, CuSO₄ 10 mM/MeCN 10:1)t_(R)=16.9 min. m.p.=320-321° C. [α]₅₄₆=+201° (c=0.5 Copper complexsolution) (lit.²+185-190° Copper complex solution preparation: SolutionA (anhydrous NaOAc dissolved in H₂O (150 mL) in 250 mL volumetric flask,glacial acetic acid (50 mL) added and diluted to volume with H₂O) mixedwith Solution B (cupric sulfate (62.5 g) diluted to volume with H₂O in a200 mL volumetric flask) in a 1 L volumetric flask and was diluted tovolume with H₂O. Metyrosine solution (5 mg/mL) was prepared in thissolution.

To obtain an NMR spectrum (taking into account the low solubility of theproduct), a small sample (10 mg) was transformed into its HCl salt. Thesample was dissolved in 2 M HCl and the solution was evaporated todryness. ¹H NMR (D₂O, 400 MHz) 1.49 (s, 3H); 2.90 (d, J=14.5 Hz, 1H);3.16 (d, J=14.5 Hz, 1H); 6.75 (d, J=8.2 Hz, 2H), 7.01 ((d, J=8.2 Hz,2H). ¹³C NMR (D₂O, 100.6 MHz) 21.6; 41.6; 61.0; 116.0, 125.0; 131.7;155.5; 173.8.

Preparation of Metyrosine using (S)-phenylethylamine

Example 7 (S)-Phenylethylamine hydrochloride

To a 500 mL flask were added (S)-phenylethylamine (BASF, ref: UN2735,40.0 g, 333 mmol, 1 eq.) and MeOH (160 mL). The solution was cooled to0° C. and 37% HCl (40 mL, 480 mmol, 1.44 eq.) were added dropwise.Concentration of the reaction mixture gave a white solid. Diethyl ether(300 mL) was added and the suspension was stirred for 15 min. The solidwas filtered and was washed with diethyl ether (2×60 mL) to provide(S)-phenylethylamine hydrochloride (39.1 g, 75%) as a white solid. ¹HNMR (D₂O, 400 MHz) 1.52 (d, J=7.2 Hz, 3H); 4.42 (q, J=7.2 Hz, 1H);7.35-7.40 (m, 5H).

Example 83-(4-Methoxyphenyl)-2-methyl-2-(1-(S)-phenylethylamino)-propionitrile

To a 500 mL flask were added (S)-phenylethylamine.HCl (25.0 g, 159.2mmol, 1 eq.), MeOH (125 mL), NaCN (7.80 g, 159.2 mmol, 1 eq.) and4-methoxyphenylacetone (Aldrich, ref: 19917-6. 24.5 mL, 159.2 mmol, 1eq.). The mixture was stirred for 14 h at room temperature. The mixturewas filtered, the filter cake was washed with MeOH (30 mL) and thefiltrates were concentrated to an oil which was dissolved in CH₂Cl₂ (370mL) and washed with water (250 mL). The organic phase was dried (MgSO₄)and concentrated in vacuo to provide3-(4-methoxyphenyl)-2-methyl-2-(1-(S)-phenylethylamino)-propionitrile(47.2 g, 100% as a 6/4 mixture of diastereoisomers (S,S)/(R,S)),containing 5% of 4-methoxyphenylacetone) as a yellow oil. ¹NMR (CDCl₃,400 MHz) 1,05 (s, 0.62×3H); 1.27 (d, J=6.4 Hz, 0.6×3H); 1.40-1.44 (m,0.4×6H); 2.47 (d, J=13.6 Hz, 0.4×1H); 2.74 (d, J=13.6 Hz, 0.4×1H); 2.84(d, J=14 Hz, 0.6×1H) 2.94 (d, J=14 Hz, 0.6×1H); 3.78 (s, 0.4×3H); 3.82(s, 0.6×3H); 4.02 (q, J=6.4 Hz, 0.6×1H); 4.16 (q, J=6.4 Hz, 0.4×1H);6.80-7.40 (m, 9H).

Example 93-(4-Methoxyphenyl)-2-methyl-2-(1-(S)-phenylethylamino)-propionamide 6

Method A. To a 1 L flask with mechanical stirring under argon was added3-(4-methoxyphenyl)-2-methyl-2-(1-(S)-phenylethylamino)-propionitrile 5(40.0 g, 136.1 mmol) dissolved in CH₂Cl₂ (400 mL). The solution wascooled to −5° C. (using an ice salt bath) and conc. H₂SO₄ (40 mL) wasadded dropwise maintaining the temperature between −5° C. and 5° C. Themixture was warmed to RT over 2 h and was stirred for 16 h. Ice (400 g)was added and the mixture was stirred for 40 min. The two phases wereseparated and the aqueous phase was neutralized to pH 8-9 with 32% aq.NH₃. The aqueous phase was extracted with EtOAc (3×350 mL). The combinedorganic layers were dried (MgSO₄) and were concentrated in vacuo toprovide 6 (14.2 g, 34%, 98% chemical purity by HPLC/MS) as a 6/4 mixtureof diastereoisomers (S,S)/(R,S)) as a yellow oil.

Method B. In a 250 mL flask was dissolved3-(4-methoxyphenyl)-2-methyl-2-(1-(S)-phenylethylamino)-propionitrile 5(5.0 g, 17.0 mmol) in CH₂Cl₂ (50 mL). The solution was cooled to 0° C.and conc. H₂SO₄ (2.5 mL) was added dropwise. The mixture was stirred at40° C. for 28 h, was cooled to RT and ice (50 g) was added. The mixturewas stirred for 1 h and the phases separated. The aqueous phase wasbasified to pH 8-9 using 32% aq. NH₃ and was extracted with EtOAc (3×50mL). The combined organic layers were dried (MgSO₄) and concentrated invacuo to provide 6 (3.32 g, 62%, 97% purity by HPLC/MS) as a 6/4 mixtureof diastereoisomers (S,S)/(R,S)) as a yellow oil. ¹H NMR (CDCl₃, 400MHz) 1.13 (s, 0.4×3H); 1.15 (s, 03×3H) 1.24 (d, J=6.6 Hz, 0.4×3H); 1.30(d, J=6.6 Hz 0.6×3H); 2.75 (d, J=13.4 Hz, 0.6×1H); 2.78 (d, J=13.6 Hz,0.4×1H); 2.84 (d, J=13.4 Hz, 0.6×1H) 3.32 (d, J=13.6 Hz, 0.4×1H); 3.78(s, 0.6×3H); 3.80 (s, 0.4×3H); 3.85 (q, J=6.6 Hz, 0.6×1H); 4.16 (q,J=6.6 Hz, 0.4×1H); 6.80-7.40 (m, 9H). HPLC/MS t_(R)=4.21 min [(S,S)-6 MS(ESI (+)) m/z 313.2 (M+1)] and 4.34 min [(R,S)-6 MS (ESI (+)) m/z 313.2(M+1)].

Example 103-(4-Methoxyphenyl)-2-(S)-methyl-2-(1-(S)-phenylethylamino)-propionamidehydrochloride

In a 500 mL flask was dissolved amide 6 (14.2 g, 45.5 mmol, 1 eq.) ini-PrOH (140 mL). Conc. HCl (5.7 mL, 68.3 mmol, 1.5 eq.) was addeddropwise and the mixture was stirred for 20 min. The solvent wasevaporated in vacuo and methyl isobutyl ketone (200 mL) was added. Themixture was heated to reflux temperature, was cooled to room temperatureand was stirred for 72 h. The solids were collected by filtration,washed with methyl isobutyl ketone (20 mL) and dried in vacuo to provide6.HCl (13.6 g, 86%, diasteremeric ratio (dr) 63/37(i.e., 63%diastereomeric purity of the S,S diastereomer)) as a white solid.

Example 11

Purification (Enhancing Diastereomeric Purity) of 6.HCl byCrystallization. In a 250 mL flask were placed amide hydrochloride 6.HCl(13.6 g, dr 37/63) and i-BuOH (136 mL). The mixture was heated to refluxtemperature and i-BuOH (95 mL) was distilled. The mixture was cooled toroom temperature and was stirred overnight. The solids were collected byfiltration and were washed with i-BuOH to provide 6.HCl (11.6 g, 85%, dr73/27 as a white solid.

This solid was dissolved in i-BuOH (139 mL) and was heated to refluxtemperature. i-BuOH (70 mL) was distilled and the mixture was cooled toroom temperature and was stirred for 3 h. Filtration provided 6.HCl (7.5g, 65%, dr 88/12) as a white solid.

This solid was dissolved in i-BuOH (130 mL) and was heated to refluxtemperature. i-BuOH (65 mL) was distilled and the mixture was cooled toroom temperature and was stirred for 3 h. Filtration provided 6.HCl (6.0g, 80%, dr 99/1) as a white solid.

This solid was dissolved in i-BuOH (105 mL) and was heated to refluxtemperature. i-BuOH (53 mL) was distilled and the mixture was cooled toroom temperature and was stirred for 16 h. Filtration provided 6.HCl(5.4 g, 90%, dr>99/1, 100% purity by HPLC/MS, 40% overall yield (67%theoretical yield)) as a white solid. ¹H NMR (DMSO, 400 MHz) 1.06 (s,3H); 1.57 (d, J=6.4 Hz, 3H); 2.84 (d, J=13.2 Hz, 1H); 3.27 (d, J=13.2Hz, 1H); 3.69 (s, 3H) 4.40 (bs, 1H); 6.83 (d, J=8.4 Hz, 2H); 6.98 (d,J=8.4 Hz, 2H); 7.37-45 (m, 2H); 7.50-7,65 (m, 2H); 7.80 (bs, 1H); 9.40(bs, 2H). HPLC/MS t_(R)=4.21 min [(S,S)-6.HCl MS (ESI (+)) m/z 313.2(M+1)].

Example 12 2-(S)-Amino-3-(4-methoxyphenyl)-2-methyl-propionamidehydrochloride

Amine 6.HCl (5.40 g, 15.5 mmol, 1 eq) was dissolved in MeOH (60 mL) and10% Pd/C (2.0 g, 56% moisture content, 16% w/w) was added. The mixturewas stirred under H₂ (3 bar) at 50° C. for 80 min. The mixture wasfiltered through celite and the filter pad was washed with MeOH (20 mL).The filtrates were concentrated in vacuo to provide2-(S)-amino-3-(4-methoxyphenyl)-2-methyl-propionamide hydrochloride(3.80 g, 100%, 99.5% purity by HPLC/MS) as a yellow solid. ¹H NMR (DMSO,400 MHz) 1.46 (s, 3H); 3.02 (d, J=14 Hz, 1H); 3.10 (d, J=14 Hz, 1H),3.72 (s, 3H); 6.87 (d, J=8.8 Hz, 2H); 7.15 (d, J=8.8 Hz, 2H); 7.64 (s,1H); 7.94 (s, 1H); 8.08 (bs, 2H). HPLC/MS t_(R)=1.95 min. MS (ESI (+))m/z=164.2 (M−CONH₂).

Example 13 Metyrosine 1

To a 100 mL flask with a reflux condenser were added2-(5)-amino-3-(4-methoxyphenyl)-2-methyl-propionamide hydrochloride(3.80 g, 15.6 mmol) and 48% HBr (20 mL). The solution was heated for 4 hat 120° C., was cooled to room temperature and was concentrated in vacuoto give a beige paste. The paste was dissolved in water (15 ml) and thesolution was again concentrated under vacuum. The paste was dissolved inH₂O (15 mL), the solution was heated to 65° C. and 300 mg of activatedcarbon were added. The mixture was stirred for 15 min, was filtered andthe filter pad was washed with water (2×4 mL). The solution was heatedto 55° C. and the pH was adjusted to 5-6 using 32% aq. NH₃. The mixturewas cooled to 0° C. and was stirred for 15 min. Filtration, washing withcold water (2×5 mL) and drying in vacuo provided Metyrosine 1 (2.55 g,83% yield, 99.6% HPLC purity, >99.5% ee) as a white solid. HPLC ((ZorbaxC18, NaH₂PO₄ 10 mM pH=3/MeCN (100:0) 10 min, (100:0) to (0:100) 15 min,0:100 5 min), t_(R)=10.1 min. Chiral HPLC (Nucleosil Chiral-1, CuSO₄ 10mM/MeCN 10:1), t_(R)=16.9 min. m.p.=321-322° C. [α]₅₄₆=+187° (c=0.5,Copper complex solution) Copper complex solution preparation: Solution A(anhydrous NaOAc dissolved in H₂O (150 mL) in 250 mL volumetric flask,glacial acetic acid (50 mL) added and diluted to volume with H₂O) mixedwith Solution B (cupric sulfate (62.5 g) diluted to volume with H₂O in a200 mL volumetric flask) in a 1 L volumetric flask and diluted to volumewith H₂O. Sample prepared 5 mg/mL in this solution.

In order to obtain an NMR spectrum and taking into account the lowsolubility of the product, a small sample (10 mg) was transformed intoits HCl salt. The sample was dissolved in 2 M HCl and the solution wasevaporated to dryness. ¹H NMR (D₂O, 400 MHz) 1.49 (s, 3H); 2.90 (d,J=14.5 Hz, 1H); 3.16 (d, J=14.5 Hz, 1H); 6.75 (d, J=8.2 Hz, 2H), 7.01(d, J=8.2 Hz, 2H).

Preparation of Metyrosine using L-alanine tert-butyl ester

Example 14

Synthesis of Aldimine. 4-Chlorobenzaldehyde (3.87 g, 27.5 mmol) wasdissolved in methanol (50 mL) and treated with triethylamine (3.87 g,38.3 mmol, 1.39 equiv). The mixture was stirred for 7 min at ambienttemperature followed by addition of L-alanine tert-butyl esterhydrochloride (5.00 g, 27.5 mmol). Magnesium sulfate (6.63 g, 55.1 mmol,2 equiv) was added to this solution and the slurry was stirred for 17 hat ambient temperature. The solid was filtered and washed with methanol(6 mL). The filtrate was evaporated to dryness to result in an oilysolid. This solid was dissolved in a biphasic MTBE/water (70 mL/20 mL)mixture. The organic phase was separated and washed with water (20 mL).The organic phase was dried over MgSO₄, the solid was filtered, and thefiltrate was evaporated to dryness to afford aldimine 7 [7.09 g; 96.2%]as a clear oil, which became a solid when stored in a refrigerator. ¹HNMR (500 MHz, CDCl₃): δ 8.25 (br. s, 1H, ArCH), 7.71 (d, J=8.5 Hz, 2H,Ar), 7.38 (d, J=8.5 Hz, 2H, Ar), 4.04 (dq, J₁=0.6 Hz, J₂=6.8 Hz, 1H,CH), 1.48 (d, J=6.8 Hz, 3H, CH₃), 1.47 (s, 9H, 3×CH₃).

Example 15

Synthesis of tert-Butyl 2-Amino-3-(4-methoxyphenyl)-2-methylpropanoate.Aldimine (2.00 g, 7.47 mmol) and O-allyl-N-benzylcinchonidinium bromide(0.38 g, 0.75 mmol, 0.10 equiv) were mixed with toluene (20 mL) atambient temperature. The mixture was stirred for 30 min and then wascooled to 0° C. Powdered KOH (2.10 g, 37.35 mmol, 5 equiv) was added atonce to convert the thin slurry into a yellow solution. The mixture wasstirred for 5 min and 4-methoxybenzyl bromide (7.51 g, 37.35 mmol, 5equiv) was added at 0 to 1° C. The solution was allowed to warm and wasstirred at ambient temperature for 16 h. The reaction mixture wassequentially washed with water (20 mL) and brine (20 mL), separated, andtreated with a 5-6 N HCl solution in IPA (7 mL) for 1 h at ambienttemperature. The reaction mixture was washed with water (20 mL). Theaqueous phase was separated and treated with toluene (20 mL). Theaqueous phase was separated, treated with a 2 N NaOH solution untilbasic, and the product was extracted with toluene (20 mL). The toluenephase was washed with brine (20 mL), separated, and dried over Na₂SO₄.The solid was filtered and the solvent was stripped to dryness to affordtert-butyl 2-amino-3-(4-methoxyphenyl)-2-methylpropanoate; 1.70 g; 85.8%as a clear oil. ¹H NMR (500 MHz, CDCl₃): δ 7.13 (d, J=8.7 Hz, 2H, Ar),6.81 (d, J=8.7 Hz, 2H, Ar), 3.78 (s, 3H, CH₃), 3.05 (d, J=13.3 Hz, 1H,CH₂), 2.71 (d, J=13.3 Hz, 1H, CH₂), 1.62 (br. s, 2H, NH₂), 1.45 (s, 9H,3×CH₃), 1.32 (s, 3H, CH₃). ¹H NMR analysis, carried out in the presenceof 1.2 equiv of BINOL, resulted in 47.6% ee. Optical rotation (α²⁵ _(D),chloroform, c=1.38): −9.06°.

Example 16

Synthesis of 2-Amino-3-(4-methoxyphenyl)-2-methylpropanoic AcidHydrochloride. Intermediate tert-butyl2-amino-3-(4-methoxyphenyl)-2-methylpropanoate (0.60 g, 2.26 mmol) wasmixed with toluene (6 mL) and a 5-6 N HCl solution in IPA (2 mL). Aclear yellow solution was heated to reflux and kept at that temperaturefor 7 h. The resulting slurry was cooled to ambient temperature andfiltered. The solid was washed with toluene (3 mL) on a filter andair-dried to afford 2-amino-3-(4-methoxyphenyl)-2-methylpropanoic acidhydrochloride [0.37 g; 67%] as a white solid [HPLC 71.8% (AUC;t_(R)=3.71]. ¹H NMR (500 MHz, DMSO-d₆): δ 13.96 (br. s, 1H, COOH), 8.44(br. s, 3H, NH₃), 7.16 (d, J=8.7 Hz, 2H, Ar), 6.90 (d, J=8.7 Hz, 2H,Ar), 3.74 (s, 3H, CH₃), 3.08 (s, 2H, CH₂), 1.48 (s, 3H, CH₃). Opticalrotation (α²⁵ _(D), DMSO, c=1.10) +7.27°.

Example 17

Synthesis of Metyrosine 1. tert-Butyl2-amino-3-(4-methoxyphenyl)-2-methylpropanoate (0.30 g, 1.13 mmol) wasdissolved in CH₂Cl₂ (3 mL) and BBr₃ (0.85 g, 3.39 mmol, 3 equiv) wasadded at room temperature. The reaction mixture was stirred for 1.5 hand treated with a NaHCO₃ solution to a basic pH. The aqueous phase wasisolated. Solid started to precipitate in the aqueous phase in 30 min.Solid was filtered in 16 h and was washed on a filter with CH₂Cl₂ (2 mL)and water (2 mL). The solid was air-dried to afford metyrosine [0.10 g;45.4%] as a white solid [HPLC 80.7% (Metyrosine; AUC; t_(R)=2.32 &2.57]. ¹H NMR (500 MHz, TFA-d): δ 8.60 (d, J=8.7 Hz, 2H, Ar), 8.39 (d,J=8.7 Hz, 2H, Ar), 4.91 (d, J=15.0 Hz, 1H, CH₂), 4.67 (d, J=15.0 Hz, 1H,CH₂), 3.30 (s, 3H, CH₃). Optical rotation (α³⁰ _(D), c=1.080, 1=10 mm,NaOAc/CuSO₄/H₂O/AcOH) +148.1.

Larger scale (e.g. >100 g) Synthesis Metyrosine using(R)-phenylglycinamide (Examples 18-24). Scheme 6 provides the generalsynthetic outline.

Example 18

2-[1-(S)-Cyano-2-(4-methoxyphenyl)-1-methylethylamino]-2-(R)-phenylacetamide2. In a 5 L reactor equipped with anchor stirrer were charged(R)-phenylglycinamide.HCl (330 g, 1.77 mol, 1 eq.), MeOH (1.1 L), H₂O(1.9 L) and p-methoxyphenylacetone (290 g, 1.77 mol, 1 eq.). A solutionof NaCN (86.7 g, 1.77 mol, 1 eq.) in H₂O (300 mL) was added over 15 minat room temperature. The mixture was stirred for 24 hours at 44° C.resulting in the formation of a yellow precipitate. The mixture wascooled to room temperature. The precipitate was filtered, was washedwith H₂O/MeOH (7:3 v/v, 2×750 mL) and i-PrOH (2×500 mL). The solid wasdried in vacuo (3 days) at 35° C. to provide2-[1-(S)-Cyano-2-(4-methoxyphenyl)-1-methylethylamino]-2-(R)-phenylacetamide2 (460 g, 80%, dr 97/3) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) 1.14(s, 3H), 2.90 (d, J=13.6 Hz, 1H), 2.99 (d, J=13.6 Hz, 1H), 3.20 (bs,1H), 3.80 (s, 3H), 4.51 (s, 1H), 5.45 (bs, 1H), 5.75 (bs, 1H), 6.90 (d,J=8.6 Hz, 2H), 7.27 (d, J=8.6 Hz, 2H), 7.30-7.50 (m, 5H). ¹H NMR (R,Rand S,S)-diastereoisomers of 2 (400 MHz, CDCl₃) 1.49 (s, 3H), 2.82 (d,J=13.8 Hz, 1H), 2,85 (d, J=13.8 Hz, 1H), 3.78 (s, 3H), 4.52 (s, 1H),5.55 (bs, 1H), 6.60 (bs, 1H), 6.84 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.6 Hz,2H), 7.30-7.40 (m, 5H). dr determination: ¹H NMR comparing integrationof peaks of 2 at 2.90/2.99 (1.00H, formally 2H) with those of its(R,R/S,S)-diastereoisomeric pair (prepared from nearlyrac-phenylglycinamide) at 2.82/2.85 (0.03H, formally 2H).

Example 19

2-[(R)-(Carbamoylphenylmethyl)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide3. Into a 10 L reactor equipped with anchor stirrer was charged CH₂Cl₂(1.64 L). The solvent was cooled to 15° C., then 95% H₂SO₄ (492 mL) and2-[1-(S)-cyano-2-(4-methoxyphenyl)-1-methylethylamino]-2-(R)-phenylacetamide2 (410 g, 1.27 mol) were added alternately in 9 portions overapproximately 45 min (specifically: 164 mL of H₂SO₄ then 82 g of 2;subsequently, at approximately 5 min intervals, 8×[41 mL of H₂SO₄ thenimmediately 41 g of 2]). On addition of each portion, the suspension of2 in the dense oily phase slowly dissolved (1-2 min) to provide abiphasic mixture. The resulting biphasic mixture (a red-brown dense oilwith a pale yellow supernatant CH₂Cl₂ layer) was stirred for 0.5 h at25° C. Ice-cold water (4.1 L) was added over 30 min, very slowlyinitially (200 mL dropwise over 15 min) due to a violent exotherm, andthe biphasic mixture was stirred for 0.5 h. The phases were separatedand the organic phase discarded. The combined aqueous phases were washedwith CH₂Cl₂ (450 mL), and residual CH₂Cl₂ was stripped from the aqueousphase by distillation under vacuum at 55° C. (20-30 mBar). The aqueoussolution was then cooled to 20° C. and was basified with 32% aq NH₃(1150 mL) to pH 8-9 at such a rate that the temperature was kept below28° C. (approximately 120 min). The suspension was stirred for 30 min toascertain a stable pH. The white solid which formed was separated byfiltration, washed with H₂O (2×2050 mL), and was thoroughly drained ofwater (but was not dried) to provide2-[(R)-(carbamoylphenylmethy)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide3 (1087 g (391 g theoretical, the sample contains 64% w/w of H₂O), yield90%, 97% HPLC purity, 96% de) as a wet white solid. HPLC (Luna C18, H₂O/ MeCN 95:5 to 0:100 30 min, 254 nm, sample 2 mg/mL in MeOH).t_(R)(3)=15.3 min, 96% de. (2 degrades under these conditions: 3 peaksare detected at 17.7, 18.9 and 19.9 min). HPLC (R,R/S,S)-diastereoisomerof 3, t_(R)=15.0 min. de determination: HPLC comparing integration ofpeaks at t_(R)=15.3 min (97.3 area % 3) and t_(R)=15.0 min (1.6 area %(R,R)-diastereoisomer of 3 (reference (R,R/S,S) prepared from nearlyrac-phenylglycinamide).

Example 20

Purification of2-[(R)-(carbamoylphenylmethyl)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide3.2-[(R)-(Carbamoylphenylmethyl)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide3 (321 g, 941 mmol) and methyl isobutyl ketone (4173 mL) were heated to72° C. until the solid was dissolved and the biphasic mixture (the minorlower aqueous layer is only visible on stopping stirring) was allowed tocool to room temperature with constant stirring. Stirring was maintainedfor 2 h. The solid formed was filtered at room temperature, was washedwith methyl isobutyl ketone (2×320 mL) and was dried in vacuo to provide2-[(R)-(carbamoylphenylmethyl)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide3 (268 g, 84%, >99.5% purity by HPLC) as a white solid. ¹H NMR (400 MHz,DMSO-d6) 1.04 (s, 3H), 2.35 (bs, 1H), 2.79 (d, J=12.8 Hz, 1H), 2.95 (d,J=12.8 Hz, 1H), 3.65 (s, 3H), 4.22 (s, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.96(d, J=8.4 Hz, 2H), 7.02 (bs, 1H), 7.05 (bs, 1H), 7.33-7.30 (m, 3H), 7.48(d, J=7.2 Hz, 2H), 7.52 (bs, 1H), 7.64 (bs, 1H). HPLC (Luna C18,H₂O/MeCN 95:5 to 0:100 30 min, 254 nm, sample 2 mg/mL in MeOH)t_(R)=15.3 min, >99.5% purity. Mp: 106-108° C.

Example 21

Hydrogenolysis to provide2-(S)-Amino-3-(4-methoxyphenyl)-2-methyl-propionamide hydrogen bromidesalt 4.HBr. To a 1 L hydrogenation reactor were added2-[(R)-(carbamoylphenylmethy)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide3 (183.0 g, 537 mmol, 1 eq), MeOH (549 mL) and 10% Pd/C (19.4 g, 5 wt%). The mixture was stirred under H₂ (3 bar) at 51° C. for 8 h. Further10% Pd/C (3.88 g, 1 wt %) was added and the mixture was stirred for afurther 8 h at 53° C. The mixture was cooled to room temperature, wasfiltered through Celite and the filter pad was washed with MeOH (2×50mL). The combined filtrates were concentrated at 30° C. under reducedpressure (rotary evaporator) to a dense white “stirrable” paste (250 mL)containing 2-(5)-amino-3-(4-methoxyphenyl)-2-methyl-propionamide 4 and5.

H₂O (75 mL) and 48% HBr (75 mL, 667 mmol, 1.25 eq.) were then addedresulting in a white suspension. Residual MeOH was stripped from themixture (45 mL distilled) by distillation at 100° C. (bath temperature)at reduced pressure (20-30 mBar). The resulting aqueous solution wascooled to room temperature and filtered; the solid was washed with H₂O(50 mL). The white solid was discarded (containing phenylacetamide 5 and4% 4.HBr by NMR) and the resulting solution of 4.HBr (approximately 400mL, containing 23% 5 with respect to 4 by NMR) was used directly. ¹H NMR(400 MHz, DMSO-6d) 4 1.14 (s, 3H), 2.10 (bs, 2H), 2.50 (d, J=13.1 Hz,1H), 2.95 (d, J=13.1 Hz, 1H), 3.69 (s, 3H), 6.80 (d, J=8.5 Hz, 2H), 6.81(bs, 1H), 6.90 (bs, 1H), 7.09 (d, J=8.5 Hz, 2H). Phenylacetamide 5 3.34(s, 2H), 7.15-7.28 (m, 6H), 7.42 (bs, 1H). HPLC (Kromasil C8, H₂O/0.1%TFA/MeCN/0.07% TFA 95:5 to 0:100 30 min, 254 nm, 1 mg/mL in MeOH)phenylacetamide 5 t_(R)=11.21 min. 4 t_(R)=9.10 min. (3 t_(R)=11.95min.).

Example 22

(−)-α-Methyl-L-tyrosine, Metyrosine 1. To a 2 L flask equipped with ananchor stirrer was charged the 4.HBr solution (519 mmol obtained fromhydrogenolysis) and 48% HBr (648 mL) was added. The solution was heatedfor 17 h at 105° C. and was cooled to room temperature. The solution waswashed with CH₂Cl₂ (8×80 mL, to remove traces of phenylacetic acid) andthe aqueous phase was stripped of residual CH₂Cl₂ by distillation at 65°C. at reduced pressure (20-30 mBar). Activated carbon (10.5 g) was addedand the mixture was stirred for 30 min at 60° C., was filtered at 60° C.and the filter pad was washed with water (2×35 mL) at RT. The combinedfiltrates were cooled to room temperature and were basified with 12.5 MNaOH (430 mL) to pH 6-7 at such a rate as to maintain the temperaturebelow 30° C. (over approximately 2 h). The white solid formed wasseparated by filtration, was washed with H₂O (2×315 mL) and was dried invacuo to provide (−)-α-methyl-L-tyrosine, metyrosine 1 (87 g,86%, >99.9% HPLC purity, no impurities detected, >99.9% ee the otherenantiomer is not detected) as a white solid. HPLC (Zorbax C18, NaH₂PO₄10 mM pH=3/MeCN (100:0) 10 min, (100:0) to (0:100) 15 min, 0:100 5 min,225 nm, sample 1 mg/mL in 0.1 M HCl) t_(R) (1)=7.6 min, t_(R) (4)=13.95min. Chiral HPLC (Nucleosil Chiral-1, CuSO₄ 10 mM/MeCN 9:1, 254 nm,sample 1 mg/mL in eluant) t_(R)=14.4 min. t_(R) enantiomer=8.4 min. Mp:309-313° C.

In order to obtain an NMR spectrum (taking into account the lowsolubility of the product), a small sample (10 mg) was transformed intoits HCl salt. The sample was dissolved in 2 M HCl and the solution wasevaporated to dryness. ¹H NMR (400 MHz, D₂O) 1.49 (s, 3H), 2.90 (d,J=14.5 Hz, 1H), 3.16 (d, J=14.5 Hz, 1H), 6.75 (d, J=8.2 Hz, 2H), 7.01(d, J=8.2 Hz, 2H).

Example 23

Transfer hydrogenolysis to provide2-(S)-Amino-3-(4-methoxyphenyl)-2-methylpropionamide formic acid salt4.HCOOH. In a 5 L reactor equipped with anchor stirrer and oil bubbler,2-[(R)-(carbamoylphenylmethyl)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide3 (261.8 g, 766.8 mmol) was dissolved in MeOH (1570 mL). A first batchof 10% Pd/C (22.2 g, 4% w/w) was added and the mixture was heated to 56°C. HCOOH (217 mL, 5.75 mol) was dissolved in H₂O (393 mL) and 480 mL ofthe resulting solution were added to the mixture dropwise over 4.5 h,and the temperature was maintained between 54 and 60° C. When gasdevelopment ceased (as determined from the oil bubbler, approximately 30min after complete addition of HCO₂H aq), the mixture was cooled to roomtemperature and a second batch of 10% Pd/C (5.6 g, 1% w/w) was added.The mixture was heated again to 55° C. and the remaining HCOOH solution(130 mL) was added dropwise over 45 min. Stirring was maintained for afurther 30 min. The mixture was cooled to room temperature, was filteredover a pad of Celite and the filter pad was washed with MeOH (2×100 mL).The combined filtrates were concentrated under reduced pressure (rotaryevaporator) to a white “stirrable” paste (approximate volume 300 mL)containing 4.HCOOH and phenylacetamide 5.

H₂O (100 mL) was added and residual MeOH was stripped by distillation atreduced pressure (20-30 mBar) at 70° C. The resulting solution(approximately 360 mL) was filtered and was washed with 100 mL of H₂O.The white solid (5 containing 1% of 4.HCOOH by NMR) was discarded andthe resulting solution of 4.HCOOH (containing 13% of 5 with respect to 4by NMR) was used directly. ¹H NMR (400 MHz, DMSO-d6) 1.43 (s, 3H), 2.93(d, J=13.6 Hz, 1H), 3.08 (d, J=13.6 Hz, 1H), 3.73 (s, 3H), 6.88 (d,J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.56 (s, 1H), 7.83 (s, 1H).Phenylacetamide 5 (200 MHz, DMSO-d6) 3.36 (s, 2H), 6.87 (bs, 1H),7.20-7.33 (m, 5H), 7.45 (bs, 1H). HPLC (Kromasil C8, H₂O/0.1%TFA/MeCN/0.07% TFA 95:5 to 0:100 30 min, 254 nm, 1 mg/mL in MeOH)Phenylacetamide 5 t_(R)=11.38 min. 4.HCO₂H t_(R)=9.11 min. (3t_(R)=11.95 min).

Example 24

(−)-α-Methyl-L-tyrosine, Metyrosine 1. Into a 2 L reactor equipped withanchor stirrer, a solution of 4.HCOOH (760 mmol from transferhydrogenolysis) and H₂O (200 mL) was mixed with 48% aqueous HBr (948 mL,8.43 mol). The resulting solution was heated to 105° C. for 17 h. Themixture was cooled to room temperature and was washed with CH₂Cl₂ (6×125mL, to remove traces of phenylacetic acid), the aqueous phase wasstripped of residual CH₂Cl₂ at 60° C. at reduced pressure (20-30 mBar).The solution was mixed with activated carbon (15.6 g, 10% w/w) and washeated to 60° C. for 30 min. The mixture was filtered at 60° C. and theresidue was rinsed with H₂O (2×60 mL). The combined filtrates werecooled to 15° C. and were basified with 12.5 M NaOH (730 mL) to pH 6-7at such a rate as to maintain the temperature below 30° C. (overapproximately 100 min). The white solid formed was separated byfiltration, was washed with H₂O (2×460 mL) and IPA (490 mL and 245 mL)and was dried to provide (−)-α-methyl-L-tyrosine, Metyrosine 1 (121.1 g,82%, >99.9% HPLC no impurities >0.1% detected; >99.9% ee., the otherenantiomer is not detected) as a white solid. HPLC (Zorbax C18, NaH₂PO₄10 mM pH=3/MeCN (100:0) 10 min, (100:0) to (0:100) 15 min, 0:100 5 min,225 nm, sample 1 mg/mL in 0.1 M HCl) t_(R) (1)=7.6 min; t_(R) (4)=13.95min. Chiral HPLC (Nucleosil Chiral-1, CuSO₄ 10 mM/MeCN 9:1, 254 nm,sample 1 mg/mL in eluant) t_(R)=14.3 min. t_(R) enantiomer=8.4 min. Mp:308-313 ° C.

While certain embodiments have been illustrated and described, it shouldbe understood that changes and modifications can be made therein inaccordance with ordinary skill in the art without departing from thetechnology in its broader aspects as defined in the following claims.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms ‘comprising,’ ‘including,’ ‘containing,’ etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase ‘consisting essentially of’ will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase ‘consisting of’excludes any element not specified.

The present disclosure is not to be limited in terms of the particularembodiments described in this application, which are intended asillustrations of various aspects. Many modifications and variations canbe made without departing from its spirit and scope, as will be apparentto those skilled in the art. Functionally equivalent methods andcompounds within the scope of the disclosure, in addition to thoseenumerated herein, will be apparent to those skilled in the art from theforegoing descriptions. Such modifications and variations are intendedto fall within the scope of the appended claims. The present disclosureis to be limited only by the terms of the appended claims, along withthe full scope of equivalents to which such claims are entitled. It isto be understood that this disclosure is not limited to particularmethods, reagents, or compounds, which can, of course, vary. It is alsoto be understood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as ‘up to,’ ‘at least,’ ‘greater than,’ ‘less than,’ and the like,include the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

Other embodiments are set forth in the following claims.

1. A process for the synthesis of a compound of Formula II:

comprising contacting in a solution a compound of Formula I:

wherein R¹ comprises C₁-C₄ alkyl with a compound of Formula

or an acid addition salt thereof, in the presence of cyanide (CN⁻), toprovide a product comprising the compound of Formula II or an acidaddition salt thereof in at least about 55% diastereomeric purity. 2.The process of claim 1, wherein R¹ is methyl.
 3. The process of claim 1further comprising contacting the product comprising at least about 55%diastereomeric purity of the compound of Formula II or an acid additionsalt thereof with a hydrolyzing agent selected from an acid, a base, ahydroperoxide, or an enzyme to provide a compound of Formula III:

or an acid addition salt thereof in about 100% diastereomeric purity. 4.The process of claim 1, in which the product precipitates from solution.5. The process of claim 3, wherein the hydrolyzing agent comprises aBrønsted acid.
 6. The process of claim 3, further comprisinghydrogenolyzing the compound of Formula III or an acid addition saltthereof to provide a compound of Formula V:

or an acid addition salt thereof.
 7. The process of claim 6, furthercomprising contacting the compound of Formula V or an acid addition saltthereof with an acid to provide a compound of Formula

or an acid addition salt thereof.
 8. A process for the purification of acompound of Formula IV-A:

comprising re-crystallizing a mixture of diastereomers of Formula IV:

or acid addition salts thereof wherein R¹ comprises C₁-C₄ alkyl toprovide the compound of Formula IV-A in at least about 70%diastereomeric purity.
 9. The process of claim 6, wherein there-crystallizing is performed using a solvent system comprising isobutylalcohol.
 10. The process of claim 6, wherein R¹ is methyl.
 11. Theprocess of claim 6, further comprising hydrogenolyzing the compound ofFormula IV-A or an acid addition salt thereof to provide a compound ofFormula V:

or an acid addition salt thereof.
 12. The process of claim 11, whereinthe compound of Formula V or an acid addition salt thereof is at leastabout 80% enantiomeric purity after isolation.
 13. The process of claim11, further comprising contacting the compound of Formula V or an acidaddition salt thereof with an acid to provide a compound of Formula

or an acid addition salt thereof.
 14. A process for the synthesis of acompound of Formula VIII:

comprising contacting a compound of Formula VI:

wherein R² comprises substituted or unsubstituted aryl and each R³comprises independently C₁-C₃ alkyl with O-allyl-N-benzylcinchonidiniumbromide, a metal hydroxide, or a metal carbonate, and a compound ofFormula VII:

wherein Z¹ comprises a leaving group and R¹ comprises C₁-C₄ alkyl toprovide a compound of Formula VIII in at least about 60% enantiomericpurity.
 15. The process of claim 14, wherein the compound provided is ofFormula:


16. The process of claim 14, wherein the compound of Formula VII is4-methoxybenzyliodide, 4-methoxybenzylbromide, or4-methoxybenzylchloride.
 17. The process of claim 14, further comprisingcontacting the compound of Formula VIII with a hydrolyzing agent toprovide a compound of Formula IX:

or an acid addition salt thereof.
 18. The process of claim 17, whereinthe hydrolyzing agent comprises a Brønsted acid.
 19. The process ofclaim 17, further comprising contacting the compound of Formula IX or anacid addition salt thereof with an acid to provide the compound ofFormula

or a salt thereof.
 20. The process of claim 19, wherein the acidcomprises a Lewis acid.
 21. An isolated stereoisomer of Formula X:

or an acid addition salt thereof; wherein: R¹ comprises C₁-C₄ alkyl; R⁴comprises —CN or —CONH₂;

R⁵ is hydrogen or R⁶ is Me or —CONH₂ provided however that if R⁶ is Methen R⁴ is —CONH₂; and wherein the stereoisomer of Formula X is at leastabout 70% diastereomerically pure after isolation; provided however thatif R⁵ is H, then the stereoisomer of Formula X is at least about 50%enantiomerically pure after isolation.
 22. The isolated stereoisomer ofclaim 21 of Formula X-A or X-B or an acid addition salt of either of thefollowing:

which is at least about 80% diastereomerically pure.
 23. The isolatedstereoisomer of claim 22, wherein R¹ is methyl.
 24. The isolatedstereoisomer of claim 22 of Formula V or an acid addition salt thereof:

which is at least about 80% enantiomerically pure.
 25. The isolatedstereoisomer of claim 24, wherein R¹ is methyl.
 26. An isolatedenantiomer of Formula XI:

or an acid addition salt thereof; wherein: R₁ comprises C₁-C₄ alkyl; R₂comprises unsubstituted or substituted aryl; each R³ independentlycomprises C₁-C₃ alkyl; R⁷ comprises —NH₂ or

and wherein the enantiomer of Formula XI is at least about 60%enantiomerically pure after isolation.
 27. The isolated enantiomer ofclaim 26 of Formula XI-A:

or an acid addition salt thereof
 28. The isolated enantiomer of claim 26of Formula XI-B:

or an acid addition salt thereof wherein R⁸ is halogen.
 29. The isolatedenantiomer of claim 25 of Formula:

or an acid addition salt thereof.